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Identification of the Gene for Scleroderma in the Tsk/2 Mouse Strain: Implications for Human Scleroderma Pathogenesis and Subset Distinctions

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Technical Report,01 Jul 2011,30 Jun 2014

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Dartmouth College Hanover United States

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This project is focused on an animal model of the human disease, systemic sclerosis SSc, called Tsk2. The SSc-like traits in Tsk2 heterozygotes are highly penetrant. With their readily apparent skin fibrosis resulting from ECM anomalies, Tsk2 mice have signs that resemble human SSc features, making it useful as a pre-clinical model. In this report, we show a clear time dependence on the gene expression in the skin of the Tsk2 mice. We have pinpointed a mutation in Col3a1 that is the Tsk2 gene, and have confirmed the sequence difference between Tsk2 and the parent strain, 101H. We present results on the expression of TGFbeta mRNA from cells cultured from Tsk2 and WT littermates that suggest a mechanism for the up-regulation of TGFbeta seen in the mutant strain. We show that elastin content in the skin, known to be controlled by TGFbeta and possibly up-regulated in SSc, is the earliest indicator of tight-skin in the tissue. Finally, we show that Tsk2 mice, and mouse fibroblasts transfected with Col3a1 from Tsk2, share a substantial fibrotic gene expression program compared to WT mice or transfectants, indicating that expression of the Col3a1Tsk2 gene alone accounts for the trait in Tsk2 mice.

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